The present invention relates to novel forms of pharmacologically active agents, and methods for the preparation and use thereof. In a particular aspect of the invention, methods are provided for treating pathological conditions with a modified form of one or more pharmacologically active agents, thereby reducing the occurrence of side-effects caused thereby.
Despite the advent of modem pharmaceutical technology, many drugs still possess untoward toxicities which often limit the therapeutic potential thereof. For example, although nonsteroid antiinflammatory drugs (NSAIDs) are a class of compounds which are widely used for the treatment of inflammation, pain and fever, NSAIDs (e.g., naproxen, aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, a side effect that remains the major limitation to the use of NSAIDs (see, for example, J. L. Wallace, in Gastroenterol. 112:10001016 (1997); A. H. Soll et al., in Ann Intern Med. 114:307319 (1991); and J. Bjarnason et al., in Gastroenterol. 104:18321847 (1993)).
There are two major ulcerogenic effects of NSAIDs: (1) irritant effects on the epithelium of the gastrointestinal tract and (2) suppression of gastrointestinal prostaglandin synthesis. In recent years, numerous strategies have been attempted to design and develop new NSAIDs that reduce the damage to the gastrointestinal tract. These efforts, however, have largely been unsuccessful. For example, enteric coating or slow release formulations designed to reduce the topical irritant properties of NSAIDs have been shown to be ineffective in terms of reducing the incidence of clinically significant side effects, including perforation and bleeding (see, for example, D. Y. Graham et al., in Clin. Pharmacol. Ther. 38:6570 (1985); and J. L. Carson, et al., in Arch. Intern. Med., 147:10541059 (1987)).
It is well recognized that aspirin and other NSAIDs exert their pharmacological effects through the non-selective inhibition of cyclooxygenase (COX) enzymes, thereby blocking prostaglandin synthesis (see, for example, J. R. Van in Nature, 231:232235 (1971)). There are two types of COX enzymes, namely COX1 and COX2. COX1 is expressed constitutively in many tissues, including the stomach, kidney, and platelets, whereas COX2 is expressed only at the site of inflammation (see, for example, S. Kargan et al. in Gastroenterol., 111:445454 (1996)). The prostagladins derived from COX1 are responsible for many of the physiological effects, including maintenance of gastric mucosal integrity.
Many attempts have been made to develop NSAIDs that only inhibit COX2, without impacting the activity of COX1 (see, for example, J. A. Mitchell et al., in Proc. Natl. Acad. Sci. USA 90:1169311697 (1993); and E. A. Meade et al., in J. Biol. Chem., 268:66106614 (1993)). There are several NSAIDs presently on the market (e.g., rofecoxib and celecoxib) that show marked selectivity for COX2 (see, for example, E. A. Meade, supra.; K. Glaser et al., in Eur. J. Pharmacol. 281:107111 (1995) and Kaplan-Machlis, B., and Klostermeyer, B S in Ann Pharmacother. 33:979-88, (1999)). These drugs appear to have reduced gastrointestinal toxicity relative to other NSAIDs on the market.
On the basis of encouraging clinical as well as experimental data, the development of highly selective COX2 inhibitors appears to be a sound strategy to develop a new generation of antiinflammatory drugs. However, the physiological functions of COX1 and COX2 are not always well defined. Thus, there is a possibility that prostagladins produced as a result of COX1 expression may also contribute to inflammation, pain and fever. On the other hand, prostagladins produced by COX2 have been shown to play important physiological functions, including the initiation and maintenance of labor and in the regulation of bone resorption (see, for example, D. M. Slater et al., in Am. J. Obstet. Gynecol., 172:7782 (1995); and Y. Onoe et al., in J. Immunol. 156:758764 (1996)), thus inhibition of this pathway may not always be beneficial. Considering these points, highly selective COX2 inhibitors may produce additional side effects above and beyond those observed with standard NSAIDs, therefore such inhibitors may not be highly desirable.
Accordingly, there is still a need in the art for modified forms of NSAIDs which cause a reduced incidence of side-effects, relative to the incidence of side-effects caused by such pharmacologically active agents in unmodified form.
In accordance with the present invention, there is provided a new class of modified NSAIDs which cause a much lower incidence of side-effects than are typically observed with unmodified NSAIDs due to the protective effects imparted by modifying the NSAIDs as described herein.
There are a number of advantages provided by modified NSAIDs according to the invention including one or more of the following:
(i) reduced irritant effects (e.g., contact irritation) of NSAIDs,
(ii) enhanced tissue delivery of the drug as a result of a decrease in net charges on the molecule, particularly for acidic NSAIDs such as naproxen, aspirin, diclofenac and ibuprofen, thereby reducing the quantity of material which must be delivered to achieve an effective dosage, and
(iii) reduction in the maximum concentration (Cmax,) achieved upon administration to a subject relative to the unmodified NSAID, while maintaining a therapeutically effective concentration of the NSAID in plasma of the subject.
In accordance with the present invention, cleavage of the modified NSAIDs described herein from the modified group appended thereto releases the pharmaceutically active agent.